Hair cells are sensitive to environmental insults such as excessive noise or chemical exposure, resulting in their death. Unfortunately, their loss in humans is irreversible. In this application, we propose to use the zebrafish mechanosensory lateral line system to study the regulation of hair cell regeneration. Lateral line hair cells share cellular and molecular properties with hair cells of the inner ear, yet are easily accessible to visualization and manipulation. We propose two screens: to search for mutations that alter hair cell regeneration and to identify small molecule regulators of regeneration. Our preliminary studies show that both screens are feasible. In initial screens, we have identified 8 mutations that alter regeneration and two compounds that enhance hair cell replacement. We propose to characterize in detail the mechanisms by which hair cell regeneration is altered by these genetic and small molecule modulators. We will also map mutations to begin identification of the molecular lesions that underlie mutant phenotypes. These studies will help us understand the regulatory pathways that control zebrafish hair cell regeneration, and may reveal the steps altered in mammals that no longer allow regeneration to occur. PUBLIC HEALTH RELEVANCE: Damage and loss of hair cells in the ear is a leading cause of deafness, and unfortunately they cannot grow back. Zebrafish have retained the ability to regenerate their hair cells after damage. Work in this proposal seeks to identify genes that regulate zebrafish hair cell regeneration and discover drugs that modulate this process, with the hopes for future therapies for hearing loss.